Pharmaceutical compositions comprising colloidal silicon dioxide

ABSTRACT

A pharmaceutical composition comprising a macrolide solid dispersion, a disintegrant and colloidal silicon dioxide, wherein the composition comprises 1 to 5% colloidal silicon dioxide by weight.

This application is a Continuation of U.S. application Ser. No.12/776711 filed May 10, 2010 which is a Continuation of U.S. applicationSer. No. 10/490089 filed Jul. 30, 2004 which is a 371 of PCT/EP02/10890filed Sep. 27, 2002 which claims benefit of G.B. 0123400.4 filed Sep.28, 2001, which in its entirety is herein incorporated by reference.

This invention relates to novel oral pharmaceutical compositionscomprising a macrolide, e.g. rapamycin or a derivative thereof or anascomycin, in a solid dispersion.

The term “macrolide” as used herein, refers to a macrocyclic lactone,for example a compound having a 12-membered or larger lactone ring. Ofparticular interest are the “lactam macrolides”, i.e., macrocycliccompounds having a lactam (amide) bond in the macrocycle in addition toa lactone (ester) bond, for example the lactam macrolides produced bymicroorganisms of the genus Streptomyces such as rapamycin, ascomycin,and FK-506, and their numerous derivatives and analogues. Such lactammacrolides have been shown to have interesting pharmaceuticalproperties, particularly immunosuppressive and anti-inflammatoryproperties.

Rapamycin is an immunosuppressive lactam macrolide that is produced byStreptomyces hycroscopicus. The structure of rapamycin is given inKesseler, H., et al.; 1993; Helv. Chim. Acta; 76: 117. See, e.g.,McAlpine, J. B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am. Chem. Soc. (1991) 113: 7433; U.S. Pat. No. 3,929,992.Rapamycin is an extremely potent immunosuppressant and has also beenshown to have antitumor and antifungal activity. Its utility as apharmaceutical, however, is restricted by its very low and variablebioavailability. Moreover, rapamycin is highly insoluble in aqueousmedia, e.g. water, making it difficult to formulate galeniccompositions. Numerous derivatives of rapamycin are known. Certain16-O-substituted rapamycin derivatives are disclosed in WO 94/02136, thecontents of which are incorporated herein by reference. 40-O-substitutedrapamycin derivatives are described in, e.g., U.S. Pat. No. 5,258,389and WO 94/09010 (O-aryl and O-alkyl rapamycin derivatives); WO 92/05179(carboxylic acid esters), U.S. Pat. No. 5,118,677 (amide esters), U.S.Pat. No. 5,118,678 (carbamates), U.S. Pat. No. 5,100,883 (fluorinatedesters), U.S. Pat. No. 5,151,413 (acetals), U.S. Pat. No. 5,120,842(silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenylderivatives) all of which are incorporated herein by reference.32-O-dihydro or substituted rapamycin derivatives are described, e.g.,in U.S. Pat. No. 5,256,790, incorporated herein by reference.

Further rapamycin derivatives are described in PCT applicationEP96/02441, for example 32-deoxorapamycin is described in Example 1, and16-pent-2-ynyloxy-32(S)-dihydrorapamycin is described in Examples 2 and3. The contents of PCT application EP96/02441 are incorporated herein byreference.

Rapamycin and its structurally related derivatives are termedcollectively as “rapamycin and rapamycin derivatives”.

The ascomycin class, of which FK-506 and ascomycin are the best knownmembers, comprise another class of lactam macrolides, many of which havepotent immunosuppressive and anti-inflammatory activity. FK-506 is alactam macrolide immunosuppressant that is produced by Streptomvcestsukubaensis No 9993. The structure of FK506 is given in the appendix tothe Merck Index, 11th ed. (1989) as item A5. Ascomycin is described,e.g., in U.S. Pat. No. 3,244,592. Many derivatives of ascomycin andFK-506 have been synthesized, including halogenated derivatives such as33-epi-chloro-33-desoxy-ascomycin described in EP 427 680. Ascomycin,FK-506 and their structurally similar analogues and derivatives aretermed collectively “ascomycin and ascomycin derivatives”.

On oral administration to humans, solid rapamycin or rapamycinderivatives, may not be absorbed to any significant extent into thebloodstream. PCT application WO 97/03654, the contents of which areincorporated herein by reference, describes pharmaceutical compositionsin the form of a solid dispersion comprising a macrolide, e.g. arapamycin, ascomycin or a derivative thereof, and a carrier medium.These compositions provide improved bioavailability of drug substance,are convenient to administer, and are stable.

However for certain groups of patients, oral administration ofmedicaments in solid tablet form is either undesirable or impractical.In particular, children and elderly patients may be unable to swallowsuch tablets conveniently. For these patients, it is typically moredesirable to provide a tablet which can first be dispersed in aningestible liquid, before consumption by the patient.

For administration to children and elderly patients, it would be highlydesirable to provide a tablet which disperses rapidly in an ingestibleliquid such as water. A problem with the prior art macrolideformulations is that, because they do not necessarily disperse rapidlyin aqueous solutions, it may be inconvenient and time-consuming toprepare a sufficiently dispersed liquid preparation beforeadministration to the patient. One particular difficulty in theformulation of a macrolide solid dispersion composition in the form of adispersible tablet is the high amount of carrier used in soliddispersion compositions, acting as a binder in tablet formulations.

It is known that a more rapidly disintegrating tablet can be produced byusing a lower compaction force during the tablet manufacturing process.However, this typically results in a tablet which has inferiormechanical properties. In particular, weakly compressed tablets showinsufficient hardness and are liable to crumble, chip or disintegratebefore this is desired (i.e. during packaging, transit, storage or atany time before addition of the tablet to an ingestible liquid forconsumption).

The present invention aims to provide a pharmaceutical composition whichalleviates the problems of the prior art compositions. Accordingly, thepresent invention provides a pharmaceutical composition comprising amacrolide solid dispersion, a disintegrant and colloidal silicondioxide, wherein the composition comprises 1 to 5% colloidal silicondioxide by weight.

The present invention is based on the surprising finding that aparticularly rapidly-dispersing composition comprising a macrolide soliddispersion can be provided by using colloidal silicon dioxide to promotedisintegration. Colloidal silicon dioxide is known from the prior artprimarily as a lubricant or flow-regulating agent in pharmaceuticalcompositions. Where it is used for such purposes, silicon dioxidetypically comprises around 0.5% by weight of the composition. Accordingto the present invention, the inclusion of 1 to 5% by weight ofcolloidal silicon dioxide has been found to be particularly effective inpromoting disintegration of a macrolide solid dispersion in an aqueoussolution, when combined with another disintegrant.

Furthermore, the compositions of the present invention show highstability and physical integrity, e.g. during storage, handling,packaging and the like, without limiting the disintegration performanceof the composition. The inclusion of colloidal silicon dioxide in asuitable amount is additionally advantageous because it results in acomposition which, when compressed into a tablet, possesses enhancedmechanical properties. In particular, tablets formed from compositionsaccording to the present invention possess a surprising combination ofrapid disintegration in aqueous solutions with mechanical stability. Fora given level of hardness, the inclusion of silicon dioxide results intablets having a faster disintegration rate. Alternatively, for a givendisintegration rate, silicon dioxide containing tablets according to thepresent invention are harder than tablets which do not contain silicondioxide.

The compositions of the present invention comprise one or moredisintegrants. Examples of disintegrants include crosslinkedpolyvinylpyrrolidone, e.g. as commercially available as Crospovidone® orPolyplasdone® (Handbook of Excipients, p. 143-144) available from ISP;sodium starch glycolate available from Generichem; and crosscarmelosesodium, e.g. as commercially available as Ac-di-sol® from FMCCorporation. Preferably the disintegrant comprises crosslinkedpolyvinylpyrrolidone.

Crospovidone® is preferably included in the composition of thisinvention in an amount of up to about 50% by weight, e.g. 10 to 30%,more preferably in an amount of about 20%, all weights based on thetotal weight of the composition.

The compositions of the present invention comprise 1 to 5% by weight ofcolloidal silicon dioxide in addition to a disintegrant as definedabove. Colloidal silicon dioxide may be obtained commercially availableas Aerosil®. Colloidal silicon dioxide, is included in the compositionof this invention in an amount from 1 to 5% of the total weight of thecomposition, preferably in an amount of 2 to 5% of the total weight ofthe composition. More preferably, the composition comprises 2 to 4% andstill more preferably 2.5 to 3.5% of colloidal silicon dioxide based onthe total weight of the composition. Most preferably the compositioncomprises about 3% of colloidal silicon dioxide by weight.

Preferably, a mixture of colloidal silicon dioxide and crosslinkedpolyvinylpyrrolidone, may be used e.g. in a ratio of from 1:1 (such asfrom 1:3) to 1:50 (such as from 1:10).

The macrolide used in the solid dispersion of this invention may berapamycin or any derivative thereof, e.g. an O-substituted derivative inwhich the hydroxyl group on the cyclohexyl ring of rapamycin is replacedby —OR₁ in which R₁ is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkylor aminoalkyl; e.g. as described in WO 94/09010, for example40-O-(2-hydroxyethyl)-rapamycin, 40-O-(3-hydroxypropyl)-rapamycin,40-O-[2-(2-hydroxyethoxy)ethyl]rapamycin, and40-O-(2-acetaminoethyl)-rapamycin. The rapamycin derivative may be a 26-or 28-substituted derivative. The rapamycin derivative may be an epimerof a derivative mentioned above, particularly an epimer of a derivativesubstituted in position 40, 28 or 26, and may optionally be furtherhydrogenated, e.g. as disclosed in WO 95/14023 and 99/15530, e.g.ABT578, or may be a rapalog as disclosed e.g. in WO 98/02441 andWO01/14387, e.g. AP23573.

Preferred rapamycin derivatives for use in this invention includerapamycin, 40-O-(2-hydroxy)ethyl rapamycin, 32-deoxorapamycin and16-pent-2-ynyloxy-32(S)-dihydrorapamycin. A more preferred compound is40-O-(2-hydroxy)ethyl rapamycin.

Numbering of rapamycin derivatives as used herein refers to thestructure disclosed as Formula A at page 4 of PCT WO 96/13273,incorporated herein by reference.

Examples of compounds of the ascomycin class are those mentioned above,e.g FK-506, ascomycin and other naturally occurring compounds, orsynthetic analogues thereof.

A preferred compound of the ascomycin class is disclosed in EP 427 680,Example 66a, also known as 33-epi-chloro-33-desoxy-ascomycin. Otherpreferred compounds are disclosed in EP 465 426, and in EP 569 337(Example 71). Particularly preferred is33-epi-chloro-33-desoxy-ascomycin.

The macrolide (e.g., rapamycin or a derivative thereof such as40-O-(2-hydroxyethyl) rapamycin or an ascomycin such as33-epi-chloro-33-desoxy-ascomycin or FK-506) is preferably present inthe composition in an amount of about 0.01 to about 30%, more preferably0.1 to 20% by weight based on the total weight of the composition. Inparticular a rapamycin derivative, e.g. 40-O-(2-hydroxy)ethyl rapamycin,may be present in the composition in an amount of 0.1% by weight.

The macrolide used in this invention, may be in crystalline or amorphousform prior to formation of the solid dispersion. An advantage,therefore, of this invention is that the macrolide need not becrystalline. Thus, the macrolide may be used directly in combination,for example with a solvent, and does not have to be isolated in advance.Another advantage of the invention is that dissolution rates of thesolid dispersion are higher than dissolution rates found for acrystalline macrolide or an amorphous macrolide in a simple mixture.

The carrier medium for the preparation of the solid dispersionpreferably comprises a carrier, e.g. a water-soluble polymer, forexample one or a mixture of the following polymers may be used:

hydroxypropylmethylcellulose (HPMC). Good results may be obtained usingHPMC with a low apparent viscosity, e.g. below 100 cps as measured at20° C. for a 2% by weight aqueous solution, e.g. below 50 cps,preferably below 20 cps, for example HPMC 3 cps. HPMC is well-known anddescribed, for example, in the Handbook of Pharmaceutical Excipients,pub. Pharmaceutical Society of Great Britain and American PharmaceuticalAssociation, 1994, pp. 229 to 232, the contents of which areincorporated herein by reference. HPMC, including HPMC 3 cps, isavailable commercially under the name Pharmacoat® 603 from the Shinetsucompany;

hydroxypropylmethylcellulose phthalate (HPMCP), e.g. as commerciallyavailable as HPMCP HP50 or HPMCP HP55;

polyvinylpyrrolidone (PVP), e.g. PVP K30 or PVP K12. PVP is availablecommercially, for example, as Povidone® (Handbook of PharmaceuticalExcipients, p. 392-399) from the BASF company. A PVP having an averagemolecular weight between about 8,000 and about 50,000 Daltons ispreferred, e.g. PVP K30;

poly(meth)acrylates, e.g. a copolymer which is resistant to gastricjuice and soluble in intestinal juices, e.g. a copolymer formed frommonomers selected from the group consisting of methacrylic acid,methacrylic acid esters, acrylic acid and acrylic acid esters, such asthose known and commercially available as Eudragit® from Röhm PharmaGmbH. An especially preferred polymer is the 1:1 or 1:2 copolymer formedfrom monomers selected from the group consisting of methacrylic acid andmethacrylic acid lower alkyl esters, such as the 1:1 or 1:2 copolymerformed from methacrylic acid and methyl methacrylate. The 1:1 copolymersare available as Eudragit® L, the 1:2 copolymers are available asEudragit® S. A particularly preferred polymer is the 1:1 copolymer ofmethacrylic acid and acrylic acid ethyl ester, commercially as Eudragit®L 100-55;

hydroxypropylcellulose (HPC) or a derivative thereof. Examples of HPCderivatives include those having low dynamic viscosity in aqueous media,e.g. water, e.g. below about 400 cps, e.g. below 150 cps as measured ina 2% aqueous solution at 25° C. Preferred HPC derivatives have a lowdegree of substitution, and an average molecular weight below about200,000 Daltons, e.g. between 50,000 and 150,000 Daltons. Examples ofHPC available commercially include Klucel® LF, Klucel® EF and Klucel® JFfrom the Aqualon company; and Nisso® HPC-L available from Nippon SodaLtd;

a polyethylene glycol (PEG). Examples include PEGs having an averagemolecular weight between 1000 and 9000 Daltons, e.g. between about 1800and 7000, for example PEG 2000, PEG 4000, or PEG 6000 (Handbook ofPharmaceutical Excipients, p. 355-361);

a saturated polyglycolised glyceride, available for example, asGelucire®, e.g. Gelucire® 44/14, 53/10, 50/13, 42/12, or 35/10 from theGattefossé company; or

a cyclodextrin, for example a β-cyclodextrin or an α-cyclodextrin.Examples of suitable β-cyclodextrins include methyl-β-cyclodextrin;dimethyl-β-cyclodextrin; hydroxyproypl-β-cyclodextrin;glycosyl-β-cyclodextrin; maltosyl-β-cyclodextrin; sulfo-β-cyclodextrin;a sulfo-alkylethers of β-cyclodextrin, e.g. sulfo-C₁₋₄-alkyl ethers.Examples of β-cyclodextrins include glucosyl-α-cyclodextrin andmaltosyl-α-cyclodextrin.

The carrier medium of the solid dispersion is present in an amount of,e.g., 0.1 to 99.99% by weight, for example 0.1 to 99.9%, e.g. 1 to 95%,e.g. 5 to 95%, e.g. 10 to 90% based on the total weight of the soliddispersion.

In one embodiment of this invention, the solid dispersion compositioncomprises 2% by weight of rapamycin or a derivative thereof, e.g.40-O-(2-hydroxy)ethyl rapamycin, and 80% by weight HPMC 3 cps.

The carrier medium for the preparation of the solid dispersion mayfurther comprise one or a combination of a water-soluble orwater-insoluble sugar or other acceptable carrier or filler such assaccharose, lactose, amylose, dextrose, mannitol, inositol, and thelike, preferably lactose; or microcrystalline cellulose, e.g.commercially available as Avicel®, Pharmacel®, Emcocell®, and Vivapur®,from FMC Corporation (Handbook of Pharmaceutical Excipients, p. 84-87).Preferably, lactose may be used.

A filler, if present, may be generally present in an amount of up toabout 50% by weight, e.g. from about 0.01 to about 50%, e.g. from about0.5 to about 40%, preferably from about 5 to about 35%, in particularabout 20%, based on the total weight of the solid dispersion.

The carrier medium may further comprise one or more surfactants, forexample a nonionic, ionic, or amphoteric surfactant. Examples ofsuitable surfactants include:

polyoxyethylene-polyoxypropylene co-polymers and block co-polymers,commercially available as Pluronic® or Poloxamer®, e.g. as described inH. Fiedler, “Lexikon der Hilfsstoffe für Pharmazie, Kosmetik andangrenzende Gebiete”, Editio Cantor Verlag Aulendorf, Aulendorf, 4threvised and expanded edition (1996), the contents of which are herebyincorporated by reference. A preferred polyoxyethylene-polyoxypropyleneblock co-polymer is Poloxamer® 188, commercially available from the BASFcompany;

ethoxylated cholesterins, commercially available as Solulan®, forexample Solulan® C24, from the Amerchol company;

vitamin derivatives, e.g. vitamin E derivatives such as tocopherolpolyethylene glycol succinate (TPGS), available from the Eastmancompany;

sodium dodecylsulfate or sodium laurylsulfate;

a bile acid or salt thereof, for example cholic acid, glycolic acid or asalt, e.g. sodium cholate; or

lecithin, e.g. soy bean phospholipid, e.g. commercially available asLipoid® S75 from Lipoid; or egg phospholipid, e.g. as commerciallyavailable as Phospholipon® 90 from Nattermann.

If present, the surfactant(s) may generally be present in an amount fromabout 0.01% to about 30% by weight, e.g. 1 to 20%, e.g. 1 to 15%, allweights based on the weight of the solid dispersion. Applicants haveobtained good results using surfactant-free solid dispersions.

In another embodiment, the carrier medium for the preparation of thesolid dispersion may comprise further additives or ingredients, e.g. anantioxidant and/or a stabilizer for example, in an amount of up to about5% by weight, for example about 0.05 to 5% by weight, e.g. 0.05 to 1%,in particular about 0.2%, all weights based on the total weight of thesolid dispersion composition. Examples of antioxidants include butylatedhydroxytoluene (BHT), butyl hydroxy anisole (BHA), DL-α-tocopherol,propyl gallate, ascorbyl palmitate, and fumaric acid. Preferably,butylated hydroxytoluene may be used. Malonic acid may be an appropriatestabiliser.

The 40-O-(2-hydroxy)ethyl rapamycin may be especially admixed with astabilizer e.g. butylated hydroxytoluene, e.g in a ratio of from 5:1. to20:1.

The carrier medium may further include antimicrobial agents, enzymeinhibitors, and preserving agents.

In another aspect, the present invention relates to a process forproducing a macrolide-containing pharmaceutical composition, comprisingpreparing a macrolide solid dispersion and mixing the macrolide soliddispersion with a disintegrant and colloidal silicon dioxide to form thepharmaceutical composition.

In the above process, the macrolide solid dispersion is first prepared.The term solid dispersion as used herein means a preparation in whichthe macrolide is in an amorphous or substantially amorphous form and isdispersed in a carrier medium. For instance, the solid dispersion may bea co-precipitate or co-evaporate of the macrolide with the carriermedium. The solid dispersion may be a composition which is adapted forfurther processing to an administrable formulation.

A. In one embodiment, the solid dispersion may be obtained by dissolvingor suspending the macrolide and carrier medium, e.g. comprising awater-soluble polymer, a filler and an antioxidant, in a solvent orsolvent mixture. The solvent may be a single solvent or mixture ofsolvents, and the order of dissolution and suspension of the macrolidewith the carrier medium in the solvent may be varied. Solvents suitablefor use in preparing the solid dispersion may be organic solvents suchas an alcohol, for example methanol, ethanol, or isopropanol; an ester,e.g. ethylacetate; an ether, e.g. diethylether; a ketone, e.g. acetone;or a halogenated hydrocarbon, e.g. dichloroethane. Preferably a solventmixture of ethanol/acetone having a weight ratio of ethanol:acetone ofbetween about 1:10 to about 10:1, e.g. 1:5 to 5:1 may be used. Typicallythe macrolide and carrier medium are present in a ratio by weight withthe solvent of 1:0.1 to 1:20. The solvent may be evaporated and themacrolide co-precipitated with the carrier medium.

B. In another embodiment, the solid dispersion may be prepared bymelting the carrier medium to form a melt, and combining the melt withthe macrolide, e.g. by stirring, optionally in the presence of a solventor solvent mixture as described herein. The resulting mixture may begranulated with a filler, e.g. lactose or mannitol.

C. In another embodiment the solid dispersion may be prepared bydissolving or suspending the macrolide and carrier medium in a solventor solvent mixture as described above, and granulating the resultingsolution/dispersion with a filler, e.g. lactose.

D. The solid dispersion may be prepared by spray-drying techniques asdescribed, for example, in Theory and Practice of Industrial Pharmacy,Lachmann et al., 1986. A solution/dispersion of the macrolide andcarrier medium in a solvent or solvent mixture as described above isdispersed through a nozzle into a chamber maintained at, e.g. 20 to 80°C., and a spraying pressure of e.g. 3 bar. The solvent is evaporatedthrough the nozzle and finely dispersed particles are collected.

E. In a further embodiment the solid dispersion may be prepared by spraygranulating the solution/dispersion of the macrolide and carrier mediumin a solvent or solvent mixture as described above onto a filler, e.g.lactose, or microcrystalline cellulose, or a mixture thereof, in a fluidbed.

In accordance with the present invention the macrolide-containing soliddispersion as described above is further processed to a pharmaceuticalcomposition in the form of a dispersible tablet. The dispersible tabletpreferably has a disintegration time of 3 minutes or less.

In an alternative aspect of this invention the solid dispersioncomposition as described above may be further processed to a rapidlydisintegrating powder or granules which may be filled into e.g. sachetsor gelatin capsules.

The resulting residues of each of the processes A to B described abovemay be sieved and milled to particles, e.g. having a mean particle sizeof less than about 0.9 mm, e.g. less than about 0.8 mm, for example lessthan about 350 microns. Preferably the particle size is at least about 5microns, e.g. about 200 to 300 microns.

The (milled) solid dispersion may be combined with colloidal silicondioxide, one or more disintegrants such as Crospovidone®, and otherexcipients, such as a filler, e.g. lactose, and blended, sieved andcombined with a lubricant, e.g. magnesium stearate, blended, and, forexample, compressed to obtain a dispersible tablet, or filled intosachets or gelatin capsules.

One or more lubricants, such as magnesium stearate, may further beincluded in the composition of this invention. Magnesium stearate may beincluded in an amount from 0.5 to 2% by weight, preferably, about 0.5%,all by weights based on the total weight of the composition.

In a particularly preferred embodiment, the pharmaceutical compositionfurther comprises a lubricant and a filler.

It may be advantageous to include one or more sweetening or flavoringagents in the compositions of this invention, e.g. in an amount of about2.5 or 5% by weight based on the total weight of the composition.

In another embodiment of this invention a water-soluble orwater-insoluble sugar or other acceptable filler such as saccharoselactose, or microcrystalline cellulose (e.g., as available as Avicel®,from FMC Corporation) may be included in the compositions of thisinvention.

Preferably lactose, in particular anhydrous lactose, may be used, e.g.in an amount of up to about 90% by weight, e.g. 20 to 80%, preferablyfrom about 50 to about 72%, all weights based on the total weight of thecomposition.

The rapidly disintegrating compositions of this invention may beadministered in any convenient form, for example in tablet, capsule,granule, or powder form, e.g. in a sachet. Preferably, the formulationis in the form of a tablet. Whereas hereinafter the compositions of theinvention are described with particular reference to tablets other typesof dosage forms may be produced and are encompassed within the scope ofthis invention.

Tablets may be produced from the compositions of the present inventionusing any suitable apparatus or procedure. Typically a tablet press isused to compress the compositions. Varying amounts of the compositionsmay be compressed in order to produce tablets of different weights. Inpreferred embodiments, 50 to 500 mg of the composition is compressedinto each tablet. More preferably, tablets are produced having a weightof about 100 mg or about 250 mg.

The force used to compress the present compositions may be varied inorder to vary the hardness and disintegration time of the resultingtablets. Use of a higher compression force results in harder tablet witha longer disintegration time. For a dispersible tablet, it is importantthat the disintegration time is sufficiently short so that the tabletcan be conveniently dispersed in an aqueous solution before consumption.Therefore it is necessary to select an appropriate compression force inorder to achieve the desired disintegration time.

However, it is also important that tablets have a sufficient degree ofmechanical strength. The present compositions are advantageous becausefor a given compression force, the resultant tablets disintegrate morerapidly in an aqueous solution than prior art tablets. Even so, thetablets of the present invention retain a sufficient degree of hardness.In order to achieve a dispersible tablet having a sufficiently shortdisintegration time using prior art formulations, a very low compressionforce would need to be used. This would produce a tablet havinginadequate hardness and mechanical properties.

It is also important to take into account the weight of the tablet whenselecting a compression force. The required level of hardness is lowerfor a smaller tablet, and a lower compression force is typically used. Askilled person could select an appropriate compression force in order toachieve the desired disintegration time for a tablet of particular size.

In one aspect the dispersible tablets of this invention have a highporosity showing rapid disintegration in an aqueous solution such aswater. The rapid dispersibility may be observed in standard tests. Thedisintegration time is preferably measured according the standard testfor dispersible tablets described in European Pharmacopoeia 4.1, page2435, (2002) in combination with European Pharmacopoeia 4, page 191,2.9.1 (2002). This test examines the disintegration time of tablets inwater at 15 to 25° C.

The dispersion may be observed visually. Disintegration is considered tobe achieved when no residue remains on the screen, or if there isresidue, it consists of a soft mass having no palpably firm, unmoistenedcore, or only fragments of coating (tablets), or only fragments of shell(capsules) remain on the screen.

The tablets of the present invention preferably have a disintegrationtime of 3 minutes or less, when measured according to the above test.More preferably the disintegration time is 2 minutes or less, still morepreferably the disintegration time is 90 seconds or less and mostpreferably the disintegration time is 30 to 65 seconds.

The hardness, or resistance to crushing, of tablets according to thepresent invention may be determined by standard tests. Tablet hardnessis preferably determined according to the standard test specified atEuropean Pharmacopoeia 4, page 201, 2.9.8 (2002). A device such as aKraemer® 3S tablet testing device may be used. This test determines theresistance to crushing of tablets, measured by the force needed todisrupt them by crushing.

The hardness of the tablets of the present invention varies according tothe weight and diameter of the tablets and the compression force. For a200 to 300 mg tablet, for example a 250 mg tablet, having a diameter ofapproximately 9 mm, the hardness is preferably 35 to 80 N. In order toachieve such a hardness, a compression force of 8 to 11 kN is preferablyapplied. For a 50 to 150 mg tablet, for example a 100 mg tablet, havinga diameter of approximately 7 mm, the hardness is preferably 25 to 60 N,and may be achieved by applying a compression force of 7 to 9 kN. Forother tablet weights and diameters, the preferred hardness varies.

Thus the advantageous properties of the present compositions may bedemonstrated by the hardness and disintegration time of tablets producedfrom such compositions. Accordingly, in a preferred embodiment thepresent invention relates to a pharmaceutical composition as definedabove, wherein 250 mg of the composition, when compressed using acompression force of 8 to 11 kN with a 9 mm die and standard flatpunches, forms a tablet having a hardness of 35 to 80 N. Preferably thecomposition is compressed using a tablet press such as a Fette® PT 2080Rotary tablet press. The hardness is measured by the standard procedurementioned above, for example using a Kraemer® 3S tablet testing device.The pharmaceutical composition is more preferably such that 250 mg ofthe composition, when compressed using a compression force of 9.5 kNwith a 9 mm die and standard flat punches, forms a tablet having ahardness of 40 to 66 N. The disintegration time of a tablet formed insuch a way from the composition is preferably 3 minutes or less, morepreferably 90 seconds or less when determined using the test specifiedabove.

In an alternative embodiment, the present invention relates to apharmaceutical composition as defined above, wherein 100 mg of thecomposition, when compressed using a compression force of 7 to 9 kN witha 7 mm die and standard flat punches, forms a tablet having a hardnessof 25 to 60 N. More preferably the pharmaceutical composition is suchthat 100 mg of the composition, when compressed using a compressionforce of 8.3 kN with a 7 mm die and standard flat punches, forms atablet having a hardness of 29 to 53 N. The disintegration time of atablet formed in such a way from the composition is preferably as givenin the preceding paragraph.

The above statements of the invention define the pharmaceuticalcomposition in terms of the properties of a particular tablet which maybe made from such a composition. However, it is clear that the inventionis in no way thereby limited to tablets having such a weight, diameter,or hardness, or only to a production process involving the use of such acompression force. As discussed, above, these values may vary fordifferent types of tablet. The above definition is rather given in orderto clarify the advantageous intrinsic properties of the presentpharmaceutical compositions, which mean that when they are formulatedinto tablets they afford a rapid disintegration time in combination witha good degree of hardness.

The tablets obtained by the compression method described above may varyin shape and be, for example, round, oval, oblong, cylindrical, flat orcurved, or any other suitable shape, and may also vary in size dependingon the concentration of the therapeutic agents.

In a preferred embodiment of the invention tablets obtained by thecompression method described above are round and flat. The edges of thetablets may be bevelled or rounded.

The compositions of this invention may be administered to a patient,such as a child, in form of a rapidly disintegrating composition, e.g. adispersible tablet, which composition may be administered together witha liquid, e.g. an aqueous medium such as water. Upon addition of theliquid to the formulation, e.g. a unit dosage form or dosage such as atablet, e.g. on a spoon, the composition, disintegrates rapidly to forma dispersion, e.g. in less than 3 minutes, preferably less than 90seconds, more preferably between 30 and 65 seconds, thus allowingconvenient administration. For administration to children, a sweeteneror other additives may be added to the aqueous medium in which thetablet is dispersed, in order to mask any unpleasant taste and to makethe dispersion more palatable.

When required, the compositions of the invention in form of a rapidlydisintegrating composition are preferably compounded in unit dosageform, e.g. as a dispersible tablet, capsule, granules or powder,preferably as a dispersible tablet. Where the composition is in unitdosage form, each unit dosage form comprising rapamycin or a derivativethereof will suitably contain between 0.05 mg and 10 mg of the drugsubstance, more preferably between 0.1 and 5 mg; for example 0.1 or 0.25mg. Such tablets are suitable for administration 1 to 5 times dailydepending upon the particular purpose of therapy, the phase of therapyand the like.

Where the composition of this invention is in unit dosage form, e.g. adispersible tablet, comprising an ascomycin, each unit dosage form willsuitably contain between 1 mg and 50 mg of the drug substance, morepreferably between 10 and 25 mg; for example 10, 15, 20 or 25 mg. Suchtablets are suitable for administration 1 to 5 times daily dependingupon the particular purpose of therapy, the phase of therapy and thelike.

The compositions of the invention may show good stabilitycharacteristics as indicated by standard stability trials, for examplehaving a shelf life stability of up to one, two or three years, and evenlonger.

The particles or granules obtained by any of the processes A to E asdescribed above may be coated, for example using an enteric coating.Suitable coatings may comprise cellulose acetate phthalate,hydroxyproyplmethylcellulose phthalate; a polymethacrylic acid polymer,e.g. Eudragit® L, S; or hydroxypropylmethyl cellulose succinate.

The tablets obtained by the compression method described above mayfurthermore be coloured, and the tablets marked so as to impart anindividual appearance and to make them instantly recognizable. The useof dyes can serve to enhance the appearance as well as to identify thecompositions. Dyes suitable for use in pharmacy typically includecarotinoids, iron oxides, and chlorophyll. Preferably, the tablets ofthe invention are marked using a code.

Procedures which may be used are known in the art, e.g. those describedin L. Lachman et al. The Theory and Practice of Industrial Pharmacy, 3rdEd, 1986, H. Sucker et al, Pharmazeutische Technologie, Thieme, 1991,Hagers Handbuch der pharmazeutischen Praxis, 4th Ed. (Springer Verlag,1971) and Remington's Pharmaceutical Sciences, 13th Ed., (Mack Publ.,Co., 1970) or later editions.

The pharmaceutical compositions of the invention are useful for the sameindications as the macrolide, e.g. rapamycin or ascomycin. Thepharmaceutical compositions of the invention comprising rapamycin or arapamycin derivative are particularly useful for:

a) treatment or prevention of cell, tissue or organ alto- orxeno-transplant rejection, for example for heart, lung, combinedheart-lung, liver, kidney, bowel, pancreatic, insulin producing cells,skin or corneal transplants. The pharmaceutical compositions are alsoindicated for the prevention of graft-versus-host disease, such assometimes occurs following bone marrow transplantation;

b) treatment or prevention of autoimmune disease and of inflammatoryconditions, in particular inflammatory conditions with an etiologyincluding an autoimmune component such as arthritis (for example,rheumatoid arthritis, arthritis chronic progrediente and arthritisdeformans) and rheumatic diseases. Specific autoimmune diseases forwhich the compounds of the invention may be employed include, autoimmunehematological disorders (including e.g. hemolytic anaemia, aplasticanaemia, pure red cell anaemia and idiopathic thrombocytopenia),systemic lupus erythematosus, polychondritis, sclerodoma, Wegenergranulomatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (including, e.g., ulcerative colitis andCrohn's disease) endocrine ophthalmology, Graves disease, sarcoidosis,multiple sclerosis, primary billiary cirrhosis, juvenile diabetes(diabetes mellitus type I), uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis, glomerulonephritis (with and withoutnephrotic syndrome, e.g. including idiopathic nephritic syndrome orminimal change nephropathy) and juvenile dermatomyositis;

c) treatment or prevention of asthma

d) treatment or prevention of chronic graft rejection or restenosis;

e) treatment of cancer, hyperproliferative skin disorder, and the like;

f) treatment of infections, e.g. fungal infections;

g) treatment or prevention of inflammation, especially in potentiatingthe action of steroids;

The pharmaceutical compositions of the invention comprising ascomycin oran ascomycin derivative are particularly useful, for example, in thetreatment of inflammatory and hyperproliferative skin diseases and ofcutaneous manifestations of immunologically-mediated diseases. Morespecifically, the compositions of this invention are useful asantiinflammatory and as immunosuppressant and antiproliferative agentsfor use in the prevention and treatment of inflammatory conditions andof conditions requiring immunosuppression, such as

a) the prevention or treatment of

rejection of organ or tissue transplantation, e.g. of heart, kidney,liver, bone marrow and skin,

graft-versus-host disease, such as following bone marrow grafts,

autoimmune diseases such as rheumatoid arthritis, systemic lupuserythematosus, Hashimoto's thyroidis, multiple sclerosis, Myastheniagravis, diabetes type I, and uveitis,

cutaneous manifestations of immunologically-mediated illnesses;

b) the treatment of inflammatory and hyperproliferative skin diseases,such as psoriasis, atopical dermatitis, contact dermatitis and furthereczematous dermatitises, seborrhoeic dermatitis, Lichen planus,Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria,angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupuserythematosus, and acne; and

c) Alopecia areata.

In a further aspect, the present invention provides use of a compositionas defined above, for the manufacture of a medicament for use as animmunosuppressant, e.g. in the treatment or prevention of one of theabove mentioned diseases or disorders.

Thus in another aspect the present invention provides a method oftreatment of a subject suffering from a disorder treatable with amacrolide, comprising administering a therapeutically effective amountof a pharmaceutical composition of the invention to a subject in need ofsuch treatment.

In another aspect the present invention provides a method ofadministering a pharmaceutical composition of the invention to a subjectin need of such therapy which comprises (i) contacting the compositionwith water and (ii) ingesting the resultant dispersion.

The dispersible tablets of this invention may be dispersed beforeingestion in e.g. 20 to 50 ml water with stirring.

The exact amount of the compositions to be administered depends onseveral factors, for example the desired duration of treatment and therate of release of the macrolide.

The compositions of the invention exhibit especially advantageousproperties when administered orally; for example in terms of consistencyand level of bioavailability obtained in standard bioavailabilitytrials. These trials are performed in animals, e.g. rats or dogs, orhealthy volunteers.

Pharmacokinetic parameters, for example absorption and blood levels,also become surprisingly more predictable and problems in administrationwith erratic absorption may be eliminated or reduced. Additionally thecompositions are effective with tenside materials, for example bilesalts, being present in the gastro-intestinal tract.

The utility of the pharmaceutical compositions can be observed instandard clinical tests in, for example, known indications of activeagent dosages giving equivalent blood levels of active agent; forexample using dosages in the range of 0.01 mg to 5 mg/kg body weight perday, e.g. 0.5 to 5 mg/kg body weight per day of rapamycin or aderivative thereof in mammals, e.g. children (e.g. below 12 years ande.g. at least 3 years) or elderly, and in standard animal models; or forexample using dosages in the range of 1 mg to 1000 mg, e.g. 2.5 to 1000mg, preferably 10 to 250 mg, per day of an ascomycin for a 75 adult andin standard animal models. The increased bioavailability of the drugsubstance provided by the compositions can be observed in standardanimal tests and in clinical trials.

Following is a description, by way of example only, of pharmaceuticalcomposition of the invention.

EXAMPLE 1 Preparation of a Solid Dispersion

A 2% solid dispersion (SD) composition is prepared containing thefollowing ingredients:

wt. (g) wt. % 40-O-(2-hydroxyethyl)-rapamycin 0.04 2.0 Butylatedhydroxytoluene 0.004 0.2 HPMC 3 cps 1.6 80.0 Lactose, monohydrate (200mesh) 0.356 17.8 Total 2.0 100

The composition is prepared by (i) mixing the40-O-(2-hydroxyethyl)-rapamycin and butylated hydroxytoluene (ii)dissolving the mixture obtained in (i) in an ethanol/acetone mixture,(iii) adding the HPMC and the lactose, (iv) homogenously dispersing themixture obtained in step (iii), and (v) removing the solvents byevaporation. The resulting residue is dried, sieved and milled.

Preparation of a Pharmaceutical Composition

A pharmaceutical composition (containing the solid dispersion describedabove) is prepared containing the following ingredients (in parts byweight):

40-O-(2-hydroxyethyl)-rapamycin SD 2% 5 Crospovidone ® 20 Aerosil ® 3Magnesium stearate 0.5 Lactose, anhydrous 71.5 Total 100

The composition is prepared by (i) blending the solid dispersion (SD),lactose, Crospovidone® and Aerosil®, (ii) sieving (0.8 mm), andblending, (iii) adding sieved (0.8 mm) magnesium stearate and blending.

Preparation of a Dispersible Tablet

A dispersible tablet is obtained by tabletting the mixture obtained instep (iii). 250 mg of the pharmaceutical composition is compressed witha Fette® PT 2080 Rotary tablet press using a compression force of 10.5kN with a 9 mm die and standard flat punches. The hardness of theresulting tablet is then assessed by measuring the force required tocrush the tablet using a Kraemer 3S tablet testing device. The hardnessof tablets manufactured under these conditions was between 35 and 79 N.The disintegration time of such tablets was 0.4 to 1.4 minutes (24 to 84seconds).

EXAMPLE 2

A pharmaceutical composition was prepared as described above. Adispersible tablet was prepared by compressing 100 mg of thepharmaceutical formulation with a Fette® PT 2080 Rotary tablet pressusing a compression force of 7.5 kN with a 7 mm die and standard flatpunches. The hardness of tablets manufactured under these conditions wasfrom 25 to 79 N. The disintegration time of such tablets was 1.1 to 1.7minutes (66 to 102 seconds).

The examples above illustrate compositions and tablets useful forexample in the prevention of transplant rejection or for the treatmentof autoimmune disease, on administration of from 1 to 5 unit dosages/dayat a dose of between 0.01 to 5 mg/kg body weight per day.

The examples are described with particular reference to40-o-(2-hydroxyethyl)-rapamycin. However, in further examples the methoddescribed in examples 1 and 2 is repeated except that40-o-(2-hydroxyethyl)-rapamycin is replaced by an alternative macrolide.The alternative macrolide may be any rapamycin derivative or ascomycinderivative mentioned above, for instance FK-506 or33-epi-chloro-33-desoxy-ascomycin. Tablets comprising such alternativemacrolides have a hardness and disintegration time which is similar tothat given above for 40-o-(2-hydroxyethyl)-rapamycin containing tablets,and are also useful as immunosuppressants.

1. A pharmaceutical composition comprising a macrolide solid dispersion,a disintegrant and colloidal silicon dioxide, wherein the compositioncomprises 1 to 5% colloidal silicon dioxide by weight.
 2. Apharmaceutical composition according to claim 1, wherein 250 mg of thecomposition, when compressed using a force of 8 to 11 kN with a 9 mm dieand standard flat punches, forms a tablet having a hardness of 35 to 80N and a disintegration time of 3 minutes or less.
 3. A compositionaccording to claim 1, wherein the composition is in the form of adispersible tablet.
 4. A composition according to claim 3, wherein thetablet has a disintegration time of 90 seconds or less.
 5. A compositionas claimed in claim 1, wherein the macrolide is rapamycin, ascomycin ora derivative thereof.
 6. A composition as claimed in claim 1, whereinthe derivative of rapamycin is 40-o-(2-hydroxy)ethyl-rapamycin. 7.(canceled)
 8. A method of administering a pharmaceutical composition ofclaim 1 to a subject in need of such therapy which comprises (i)contacting the composition with an aqueous solution (ii) allowing thecomposition to disperse in the aqueous solution to form a dispersedmixture and (ii) ingesting the dispersed mixture.
 9. (canceled)
 10. Aprocess for producing a macrolide-containing dispersible tablet,comprising preparing a macrolide solid dispersion, mixing the macrolidesolid dispersion with a disintegrant and colloidal silicon dioxide toform a pharmaceutical composition and compressing the pharmaceuticalcomposition to form the dispersible tablet.